ALKYLATING AGENTSRELATEDTO 2,2’-BIAZIRIDINE. I
July 1967
697
Alkylating Agents Related to 2,2‘-Biaziridine. I. Compounds Derived from 1,4-Diamino-2,3-butanediol PETER W. FEITAND OLE TVAERMOSE XIELSEX Leo Pharmaceutical Products, Ballerup, Denmark Received Sovember 1l+,1966 Revised Jranuscript Receavecl February 27, 1967 The synthesis of meso-, DL-, and (28:38)-1,4-diaminobutane-2,3-bissulfuricacid (S), and meso-, DL-, and ( 2 8 :3S)-1,4-diamino-2,3-butanediol 2,3-bismethanesulforiate (11) is described. The rem011 for the interest in this type of alkylating agents is discussed, and the anticancer screening data for the compounds are qummarized. The structure of meso-diaminobutanediol and its derivatives previously described id revised.
Over the past two decades intense interest in aziridines and the related mono- and bifunctional nitrogen mustards as possible anticancer drugs has led to the preparation and evaluation of various analogs and derivatives in the search for enhanced anticancer properties. However, most investigations were made to find carrier molecules for the alkylating groups, which could influence the alkylating properties, the biological transport, or lead to an accumulation in the target tissue, in order to reach increased therapeutical indices. From pharmacological and therapeutical points of view the reported results mere rather disapp0inting.l However, me considered it desirable to synthesize alkylating agents which may be considered in vivo precursors for the unlinown 2,2’-biaziridine (1, R = H) or Ssubstituted biaziridines 1 including the “activated R
r / \
R
x
/-\
CH9-CH-CH-CH2 1
type”* of aziridines. Furthermore, we wished to invest’igate some of the corresponding S-substituted biaziridines. Our initial interest in this type of compounds was based on the antineoplastic activity3 of (2S:3S)threit’ol 1,4-bi~methanesulfonate,~~~ Lvhich might act after in vivo transformation to epoxy compounds, since the transformation to (2s: 3S)-1,2:3,4-diepoxybutane [(S:S)-4]is proved to proceed in vitro under physiological conditions,6 and furthermore on the acceptance that nitrogen mustards probably involve aziridine or aziridinium compounds as reactive intermediates in vivo as recently reinvestigated in vitro by nmr studies.? Compounds of the general formula 1, and consequently their possible precursors, can exist in three (1) L. 11. Schmidt, R. Fradkin, R. Sullivan, and A . Flowers. Cancer Chemotherapy Rept., Suppl. 1, 1 (1965). (2) G . E . H a m , J . Org. Chem., 29, 3062 (1964). (3) (a) R. Jones, \V. B. Kessler. H. E. Lessner, and L. Rane. Cancer Chemotherapy Rept., 10, 99 (1960); (b) F. R . White. ibid., 24, 95 (1962); ( c ) V. Loeb, Jr., ibid., 42, 39 (1964). (4) P. W.Feit, J . Med. Chem., ‘7, 14 (1964). ( 5 ) Earlier4 t h e configuration of this compound was designed by the prefix L. I n this paper t h e Cahn-Ingold-Prelog system is used for t h e optically active compounds t o avoid confusion since t h e papers of this series concern compounds which could be based on the configuration of either glycerolaldehyde or serine: R. S. Cahn, C. K. Ingold, and V. Prelog, Angew. Chem., 78, 413 (1966). and preceding papers. (6) W. Davis and W, C. J. Ross, Biochem. Pharmacol., 12, 915 (1963). ( 7 ) P. L. Levins and Z. B. Papanastassiou, J . A m . Chem. Soc.. 8’7, 826 (1965).
optical isomers. I n order to get acceptable information about the biological activities, it appeared important to us to attempt the preparation of the vieso isomers, one of the optically active isomers, arid the racemates of the desired compounds, since optical stereospecificity of anticancer agents has been denionstrated even when alkylating agents are involved.8 In the present paper the synthesis of derivatives 9 and 11 of 1,4-diamino-2,3-hutanediol as possible in vivo precursors of the corresponding 1 (R = H) is reported (Table I). Attempts to isolate the expected biaziridine 1 (R = H) after alkali treatment of both 9 and 11 were unsuccessful. Chemistry.-IGlmer and ?\IcI
